AMP-activated protein kinase and the metabolic syndrome.

The occurrence of Type II (non-insulin-dependent) diabetes and obesity and their associated morbidities continue to increase and they are rapidly reaching epidemic proportions. AMPK (AMP-activated protein kinase) was initially thought of as an intracellular 'fuel gauge' responding to a decrease in the level of ATP by increasing energy production and decreasing energy utilization. Recent studies have shown that AMPK plays a role in controlling the whole body energy homoeostasis, including the regulation of plasma glucose levels, fatty acid oxidation and glycogen metabolism. In addition to its effects on the periphery, AMPK has been found to play a key role in the control of food intake through its regulation by hormones, including leptin, within the hypothalamus. The control of AMPK activity, therefore, provides an attractive target for therapeutic intervention in metabolic disorders such as obesity and Type II diabetes. Indeed, a number of physiological and pharmacological factors that are beneficial in these disorders have been shown to act, at least in part, through the activation of AMPK.

Bypassing the glucose/fatty acid cycle: AMP-activated protein kinase.

The AMPK (AMP-activated protein kinase) cascade plays a key role in regulating energy metabolism. Conditions which cause a decrease in the ATP/AMP ratio lead to activation of AMPK. Once activated, AMPK initiates a series of responses that act to restore the energy balance of the cell. In skeletal muscle, activation of AMPK increases both glucose uptake and fatty acid oxidation, raising the possibility that AMPK can bypass the glucose/fatty acid cycle. This review focuses on the role of AMPK in the regulation of glucose and fatty acid metabolism in muscle. Recently, naturally occurring mutations within the gamma isoforms have been identified which lead to altered metabolic regulation in cardiac and skeletal muscle and suggest an important role for the kinase in regulating glycogen metabolism.